Histones associate with DNAs in the nuclei of eukaryotic cells as basic proteins and are subject to reversible acetylation at the amino group of the lysine residue. Such reversible acetylation of histones is involved in the formation of chromatin of a higher order structure, the cell division cycle and ultimately the gene expression, and can be regulated by the dynamic balance established between the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs): these enzymes neutralize or restore the positive charges of lysine residues (e.g., 4 lysine residues in H4) by acetylation/deacetylation to regulate the gene transcriptional level.
HDACs play an important role in cell cancerization or differentiation and their expression is enhanced under conditions such as hypoxia, lowered glucose, and cell cancerization, to inhibit the expression of cell proliferation inhibitors. That is, histone deacetylation by HDAC causes cell proliferation, while hyperacetylation of histone facilitates the inhibition of cell proliferation and cell differentiation. Therefore, when HDACs are inhibited, cell proliferation and angiogenesis can be controlled.
Abnormal histone deacetylation has been reported to cause acute promyelocytic leukemica (APL) (Lin R. J. et. al. Oncogene 20: 7204, 2001; Zelent A. et. al. Oncogene 20: 7186, 2001). Specifically, abnormality in the regulation of HDAC activity leads to oncoprotein's inadequate transcriptional suppression and the formation of abnormal chromatin structures, which causes normal cells to become cancer. Accordingly, HDAC has been one of targets for the study of anticancer drugs as well as gene expression inhibitors and there have been attempts to develop HDAC inhibitors as anticancer drugs.
Recent studies on anticancer drug through chromatin remodeling have shown that HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA) or apicidin inhibit the proliferation of cancer cells and induce cell differentiation (Munster P. N. et al., Cancer research 61: 8492, 2001; Han J. W. et. al. Cancer research 60: 6068, 2000).
n-Butyrate, used as the first HDAC inhibitor, was reported to be useful for the treatment of large intestine cancer as well as molecular biology test. But it is not suitable for the analysis of a HDAC inhibitor due to its high concentration in the order of millimole (mM), and influence on other enzymes in cells, cytoskeleton, cell membrane, etc. Trichostatin A (TSA) which enhances the differentiation and suppresses the proliferation of Friend murine erythroleukemia cells has been reported to inhibit HDAC (Yoshida M. et al., Cancer research 47: 3688, 1987; Yoshida M. & Beppu T. Exp. Cell Res. 177: 122, 1988; Yoshida M. et al., J of Biol. Chem. 265: 17174, 1990).
Therefore, there has been a need for developing an improved HDAC inhibitor. The present inventors have found that novel naphthalenyloxypropenyl derivatives are efficient inhibitors against cell proliferation which can be advantageously used for treating cancer.